1. Field of Invention
This invention relates to combination products comprising low doses of oral anticoagulants, such as warfarin, and low doses of inhibitors of platelet function (e.g., aggregation, adhesion) such as non-steroidal antiinflammatory agents, and preferably aspirin, in a single dosage form. Further, this invention relates to methods of using these low dose combination products for the prevention and/or treatment of first or recurrent myocardial infarction or the prevention and/or treatment of first or recurrent stroke.
2. Background Information
Recent advances in the understanding of the pathogenic factors leading to the acute coronary ischemic syndromes of unstable angina, myocardial infarction and ischemic sudden death, and acute cerebrovascular ischemic syndromes like transient ischemic attacks and stroke have demonstrated the individual importance of two compounds in particular, acetyl salicylic acid, hereinafter referred to as aspirin or ASA, and warfarin, in the prevention and/or treatment of these syndromes. Recently the value of antithrombotic therapy with high-dose aspirin in unstable angina has been conclusively demonstrated by two randomized, placebo-controlled, double-blind trials. See generally Lewis, et al. "Protective Effects of Aspirin Against Acute Myocardial Infarction and Death in Men with Aspirin " Results of a Veterans Cooperative Study, New England Journal of Medicine, 309: 396 (1983) and Cairns, et al.: "Aspirin, Sulfinpyrazone or Both in Unstable Angina: Results of a Canadian Multicenter Trial". New England Journal of Medicine, 313: 1369, (1985). Also, the recently pooled results of several studies suggest that long-term high-dose oral anticoagulant therapy may reduce the rate of recurrence of myocardial infarction by about 20%. [Fuster, et. al, (1988) Perspective, "Insights into the Pathogenesis of Acute Ischemic Syndromes", 77, No. 6, pp 1213-1220].
Since currently available pharmaceutical products have an isolated inhibitory effect on either platelet function or thrombus formation, the use of a combination of agents which would effect both platelet aggregation/adhesion and thrombus formation simultaneously, provides a potential benefit of improved efficacy at lower dosages over the use of individual agents. Since aspirin may prevent ischemic cardiac events caused by coronary artery disease and oral anticoagulants may protect against both ischemic cardiac events and resultant cerebral embolization from ventricular thrombi, the combination in small doses may provide the best overall protection. [Fuster, V., Halperin, J. L., (1989) The New England Journal of Medicine, Feb. 9, 1989, pp 392-394.]
Traditionally, the simultaneous use of warfarin and aspirin at high doses has been relatively contraindicated. It has been a pervasive practice in the medical community to use these agents on an either/or basis. This practice was largely due to medical literature reporting undesirable clinical and pharmacologic interactions of the two drugs at high doses. Clinically, the propensity of aspirin, at high doses, to cause gastric mucosal erosion/ulceration, when dosed with an oral anticoagulant (warfarin) has led to a high reported incidence of exaggerated gastrointestinal (GI) bleeding with the high dose combination. Pharmacologically, aspirin at high doses also acts synergistically with warfarin to elevate the prothrombin time assay level for a given dose of warfarin. In light of recent advances in the study of the acute coronary syndromes and the recognition of the individual benefits that aspirin and warfarin provide in treating and/or preventing these syndromes, there is a need for a combination product wherein an oral anticoagulant such as warfarin and an antiplatelet agent, such as aspirin or a non-aspirin-non-steroidal antiinflammatory agent are present in a low dose ratio. The combination permits the use of doses below those currently accepted as "therapeutic" in the medical literature, in other words, doses at which the beneficial effects of the two agents are favored over the dose related side effects associated with simultaneous administration of currently accepted, high doses of the two agents.